General Information

Fosrenol is a chewable tablet formulation which delivers the
carbonate salt of the element lanthanum. This salt dissolves freely
in the acid of the digestive tract, yielding ionic lanthanum, which
has been shown to bind dietary phosphate released from food during
digestion. This binding actvity prevents the dietary absorption of
phosphate in the intestines.

Fosrenol is indicated to reduce serum phosphate levels in
patients with kidney dysfunction due to end-stage renal disease
(ESRD) when taken with or immediately following meals. By
preventing absorption of gastric phosphate, the burden of phosphate
regulation on the kindeys is lowered. In addition, because only a
very small percentage of Fosrenol is absorbed into the blood
stream, it does not place significant additional burden on
metabolic systems of the liver or elimination systems in the
kidneys.

Fosrenol is supplied as a chewable tablet of two dosage
strengths (250 mg and 500 mg), and is designed to be taken with or
immediately following meals. The recommended initial total daily
dose is 750-1500 mg, and dosing should be titrated every 2-3 weeks
until optimum serum phosphate levels are achieved. Most in clinical
trials patients needed total daily doses of 1500-3000mg.

Clinical Results

FDA approval of Fosrenol for the treatment of hyperphosphatemia
in ESRD was based on a total of 5 clinical trials: 3 were placebo
controlled, including 1 short-term, double-blind dose-ranging study
and 2 randomized withdrawal studies; and 2 were active-controlled,
both long-term, open-label studies in both hemodialysis and
peritoneal dialysis (PD) patients.Placebo Controlled Studies
Short-Term Study
144 hyperphosphatemic patients with chronic renal failure
undergoing hemodialysis were randomized to double-blind treatment
at a fixed dose of lanthanum carbonate of 225 mg (n=27), 675 mg
(n=29), 1350 mg (n=30) or 2250 mg (n=26) or placebo (n=32) in
divided doses with meals for 6 weeks. Mean age was 56 years, and
the duration of dialysis experience ranged from 0.5 to 15.3 years.
Results indicated that the drug reduced serum phosphate levels in a
dose-dependent manner, with steady state levels achieved after 2
weeks.

Long Term Withdrawal Studies
185 patients with ESRD undergoing either hemodialysis (n=146) or
peritoneal dialysis (n=39) were enrolled in 2 randomized withdrawal
studies. Mean age was 58.4 years and the duration of dialysis
ranged from 0.2 to 21.4 years. All subjects receved titrated doses
of Fosrenol until target phostphate levels were reached (4.2-5.6
mg/dl in one study or < 5.9 mg/dl in the second) and maintained
for 6 weeks. Following this steady state, patients were randomized
to receive Fosrenol or placebo during a 4 week withdrawal period.
Results indicated that subjects receiving Fosrenol maintained
steady-state serum phosphorus levels, but subjects receiving
placebo experienced significant increases in serum phosphate levels
(1.9 mg/dl in both studies) back to the range of hyperphosphatemia
(>6.0 mg/dL).

Open Label Studies 2 long-term studies
were conducted, involving a total of 2028 patients with ESRD on
hemodialysis. Patients were randomized to receive Fosrenol or
alternative phosphate binders to investigate the drug's
efficacy in long term treatment (up to 6 months for study 1, and 2
years for study 2). Subjects receiving Fosrenol were treated with
titrated regimens based on doses needed to achieve target serum
phosphate levels (total daily doses: 375 mg-3000 mg). Regimens of
active controll medicines followed current prescribing guides or
common standards. Fosrenol demonstrated a non-inferior reduction in
serum phosphate levels (roughly 1.8 mg/dL for all medications), and
maintenance of these levels with Fosrenol was extablished for up to
three years in long-term, open label extensions.

Safety Data
Fosrenol demonstrated an excellent safety and tollerability, due to
its very low rate of systemic absorption. Preclinical animal
studies indicated that 94%-99% of the drug passed completely
through the intestinal tract, and clinical experience demostrated
no systemic metabolism, no significant changes in liver function,
no drug-related effects of on vitamin absorption (other than
phosphate) in patients monitored for 6 months, and no differences
in the development of mineralization defects in bone density scans
between Fosrenol and placebo or approved therapies.

Side Effects

Adverse events associated with the use of Fosrenol may include
(but are not limited to) the following:

Nausea

Vomiting

Dialysis Graft Occlusion

Diarrhea

Headache

Abdominal Pain

Hypotension

Constipation

Mechanism of Action

Fosrenol is a carbonate salt of the rare-earth metal lanthanum.
This salt dissociates in the acid of the stomach to release
lanthanum ions that bind dietary phosphate released from food
during digestion. Binding phosphate ions forms highly insoluble
lanthanum-phosphate complexes, which are not absorbed in the rest
of the GI tract. Dietary phosphate thus cannot contribute to serum
phosphate levels, allowing the kidneys to reduce these levels to
normal reanges. Lower serum phosphate levels also reduce the
prodution of calcium phosphate, high levels of which can lead to
ectopic calcification.